More than a Cleanup Crew: the Expanding Biology of Efferocytosis

Abstract

Efferocytosis, the process by which phagocytes clear apoptotic cells, is essential for tissue homeostasis, inflammation resolution, and repair. Once considered a passive waste-disposal process, efferocytosis is now recognized as a dynamic, immunometabolic program that integrates apoptotic cell clearance with metabolic reprogramming and inflammation resolution. In cardiovascular contexts, efficient efferocytosis limits necrosis, enhances the deposition of wound healing matrix proteins, and promotes tissue healing, while impaired clearance drives chronic inflammation and maladaptive tissue remodeling. We review the molecular mechanisms governing efferocytosis, including the interplay of “find-me”, “eat-me”, and “don’t-eat-me” signals with receptor-mediated cytoskeletal remodeling and lysosomal degradation. We highlight how efferocytosis drives lipid efflux, fatty acid oxidation, amino acid catabolism, and nucleotide recycling, processes that sustain continual efferocytosis and resolution programming. Defects in these pathways, amplified by proteolytic cleavage of apoptotic cell receptors, dysregulated metabolism, and inflammatory mediators, underlie impaired efferocytosis in atherosclerosis, myocardial infarction, vascular aging, and metabolic diseases. Finally, we discuss emerging concepts, including non-professional phagocyte contributions, crosstalk with adaptive immunity, and therapeutic strategies to enhance efferocytosis or preserve receptor integrity. Collectively, these insights redefine efferocytosis as more than a cleanup mechanism, positioning it as a central contributor to attenuating cardiometabolic diseases.

Introduction

The efficient clearance of apoptotic cells (ACs) is an evolutionarily conserved process responsible for preserving tissue architecture, limiting inflammation, and promoting repair¹. This process, termed “efferocytosis”, relies on the expression of specific receptors that recognize “eat-me” signals on the surface of dying cells. Following AC recognition, phagocytes reorganize their cytoskeleton to engulf the dead cell for degradation in the phagolysosome. Subsequently, phagocytes initiate downstream signaling cascades that control inflammatory responses, production of cytokine and lipid mediators, and cellular metabolism.

In cardiometabolic diseases, efficient clearance of dead cells takes on particular significance. The heart and vasculature are subject to high energy demands, and efferocytosis plays a crucial role in maintaining homeostasis and responding to damage. In atherosclerotic plaques, efficient efferocytosis by macrophages attenuates expansion of necrotic cores and limits inflammation, both of which contribute to plaque growth and risk of plaque rupture^2,3. During ischemic cardiovascular events, such as myocardial infarction, clearance of apoptotic cardiomyocytes is vital for limiting tissue damage, resolving inflammation, and initiating tissue repair processes⁴. Understanding how efferocytosis operates in different disease settings remains a major challenge, one with direct implications for developing therapies that target inflammation and repair. This review will explore efferocytosis as a complex immunometabolic program at the intersection of cell death, immune modulation, and tissue adaptation. We will discuss basic mechanisms of efferocytosis, how efferocytosis drives metabolic and inflammatory reprogramming, the impact of impaired efferocytosis in cardiometabolic diseases, and present emerging concepts and potential therapeutic approaches.

Molecular Mechanisms of Efferocytosis

Efferocytosis is a multi-step process by which phagocytes, most prominently macrophages, recognize, engulf, and degrade ACs. This process is indispensable for maintaining tissue homeostasis and preventing post-apoptotic necrosis, which would otherwise release damage-associated molecular patterns (DAMPs)^5,6. Clearance of ACs is highly orchestrated and involves four major stages⁷: (1) migration of phagocytes toward ACs in response to “find me” signals, (2) recognition of ACs through “eat-me” ligands and bridging molecules, (3) receptor-mediated cytoskeletal rearrangements to drive internalization, and (4) lysosomal degradation within the phagolysosome^2,8,9.

To mediate macrophage recruitment, ACs produce chemoattractants termed “find me” signals. These include nucleotides, such as ATP and UTP, the chemokine CX3CL1, and lipids, such as sphingosine-1-phosphate (S1P) and lysophosphatidylcholine (LPC)^10–13. Nucleotides are released through pannexin-1 channels that open during apoptosis¹⁴. CX3CL1 (fractalkine) is proteolytically shed from the AC surface by ADAM metalloproteinases and binds to CX3CR1 on efferocytes¹⁵. S1P, generated via sphingosine kinase activation, binds S1PR1–5 and supports macrophage chemotaxis into tissues with high apoptotic burden¹³. LPC, generated by caspase-activated iPLA2, signals through G2A receptors and reinforces recruitment¹⁶. Annexin A1, another find-me signal, acts through formyl peptide receptor 2 (FPR2/ALX) and links AC recognition to the resolution of inflammation¹⁷.

Once recruited, phagocytes must distinguish ACs from viable cells. This is achieved by the balance between pro-engulfment “eat-me” signals and inhibitory “don’t-eat-me” ligands¹⁸. During apoptosis, caspase-mediated activation of scramblases flip PtdSer to the outer leaflet, creating a strong engulfment cue^19,20. In parallel, calreticulin is translocated to the surface of ACs, where it can act as an eat-me signal²¹. Oxidatively modified lipids, including oxidized PtdSer and phosphatidylcholine, also accumulate on apoptotic membranes and can be recognized by scavenger receptors²². Counterbalancing these are don’t-eat-me signals such as CD47^23,24. CD47 interacts with signal regulatory protein α (SIRPα) on macrophages, leading to recruitment of the SHP-1 and SHP-2 phosphatases, which suppress Rac1 activity and inhibit cytoskeletal rearrangement^25–27. Thus, the decision to engulf depends on the dynamic integration of pro- and anti-phagocytic cues.

AC recognition is mediated by a panoply of macrophage receptors that either bind directly or indirectly via bridging molecules. Direct receptors include BAI1, members of the TIM family (TIM1, TIM3, and TIM4), and Stabilin 1 and 2¹. BAI1 is a seven-pass transmembrane protein that binds PtdSer through thrombospondin type 1 repeats and couples to the intracellular ELMO1-Dock180 complex²⁸. This GEF activates Rac1, driving actin polymerization for engulfment. TIM family members also bind PtdSer, with TIM4 functioning mainly as a tethering receptor, while TIM1 and TIM3 can deliver signals to promote phagocytosis¹. Stabilin-2 engages PtdSer and signals via the adaptor GULP, which activates Rac1¹. The TAM family (Tyro3, AXL, MerTK) of receptor tyrosine kinases recognize ACs through their ligands Protein S and Gas6, which bind PtdSer via their γ-carboxyglutamic acid domains²⁹. Activation of TAM receptors activate PI3K/Akt and ERK1/2 as well as activating Rac1^29,30. LRP1 and CD36 are also dependent on bridging molecules, including thrombospondin-1, and complement C1q. Another bridging molecule, MFG-E8, binds PtdSer on ACs and αvβ3/αvβ5 integrins on macrophages, promoting tethering and internalization³¹.

As mentioned above, efferocytosis requires actin cytoskeletal remodeling to drive internalization of an AC. Activated Rac1 promotes lamellipodia formation and actin branching via WAVE1-dependent stimulation of the ARP2/3 complex, driving pseudopod extension around an AC³². This activity is balanced by RhoA-mediated contractility. Although RhoA is traditionally viewed as antagonistic to engulfment, it is required for cup closure through ROCK-mediated phosphorylation of myosin light chain, generating actomyosin contraction³³. Thus, Rac1-mediated extension and RhoA-driven contractility are highly coordinated events that promote rapid AC internalization.

Following internalization, the nascent phagosome undergoes maturation into a degradative compartment. Rab5 GTPase promotes early phagosome fusion with sorting endosomes, while Rab7 coordinates transition to late endosomes and lysosomal fusion^34,35. A defining feature of AC-containing phagosomes is LC3-associated phagocytosis (LAP), which stabilizes the phagosome, prevents premature leakage of AC contents, and promotes efficient fusion with lysosomes³⁶. Within the resulting LAPosome, cathepsins degrade proteins, DNase II digests DNA, and lipases process lipids³⁷. This degradation not only prevents the release of DAMPs but also generates metabolites that can be recycled for macrophage metabolism and resolution programming³⁸. Simultaneously, upon uptake of apoptotic cells, macrophages activate DRP1-mediated mitochondrial fission, thereby enhancing cytosolic calcium levels³⁹. This increase in cytosolic calcium supports vesicular trafficking and phagosome sealing, enabling efficient internalization of subsequently-encountered apoptotic cells³⁹.

Efferocytosis-Driven Metabolic and Inflammatory Reprogramming

Within the phagolysosome, pH-dependent hydrolysis liberates AC-derived cargo in quantities that would overwhelm the phagocyte if not properly managed⁶. To address this challenge, macrophages have evolved a specialized program of metabolic adaptation, termed “efferotabolism”⁶. This process refers to the capacity of efferocytic macrophages to metabolize, efflux, or re-route AC-derived cargo in ways that sustain continual efferocytosis and promote the production of pro-resolving mediators.

Lipid and fatty acid handling:

Sterols are sensed by nuclear receptors, especially the liver X receptor (LXR) and peroxisome proliferator-activated receptors (PPARs)⁴⁰. Activation of this axis promotes transcription of ABCA1 and ABCG1, thereby linking engulfment directly to lipid export^41,42. Signaling downstream of the engulfment receptor BAI1 can also induce ABCA1, but in an LXR-independent, Rac1-dependent manner⁴³. Notably, cholesterol efflux has direct consequences for inflammatory signaling. By lowering intracellular cholesterol, macrophages reduce the propensity for cholesterol crystal formation, inflammasome activation, and caspase 1-mediated release of IL-1β and IL-18^44,45. In parallel, macrophages shunt excess free cholesterol into the ER, where acyl-CoA:cholesterol acyltransferase (ACAT) esterifies it into inert cholesterol esters⁴⁶. This process mitigates the membrane-disruptive effects of free cholesterol, effectively buffering the cell against lipotoxicity. The immunoregulatory receptor TREM2 adds another dimension to lipid metabolism. TREM2 signaling enhances lipid uptake and supports the survival of foam cell-like macrophages, thereby sustaining their efferocytic function⁴⁷. Importantly, Trem2 expression is also associated with efferocytosis, suggesting that it fine-tunes a balanced state in which lipid-rich macrophages resist necrosis while also maintaining resolution^48,49. Interestingly, AC-derived fatty acids enter mitochondria for β-oxidation once they are released into the cytosol (Figure 1). This oxidative process increases intracellular NAD+, which activates the deacetylase SIRT1⁵⁰. In turn, SIRT1 deacetylates and activates PBX1, a transcription factor that promotes IL-10 expression (Figure 1)⁵⁰. Thus, fatty acid oxidation (FAO) provides a direct metabolic route from engulfment to the induction of pro-resolving cytokines, with inhibition of FAO blocking efferocytosis-induced IL-10 production⁵⁰.

Figure 1: Mechanisms and consequences of efferocytosis and efferotabolism.

Macrophages interact with ACs either directly or indirectly. The successful interaction between these cells generates a downstream signaling cascade that stimulates ELMO-DOCK180 or GULP, among others, to activate Rac1. LAP promotes lysosome and phagosome fusion to form a phagolysosome, where the pH-dependent activation of enzymes (protease, nuclease, and others) ensures the degradation of an AC into basic cellular components. The cargo derived from ACs is either effluxed or fueled into signaling pathways that promote continual efferocytosis and production of pro-resolving mediators while decreasing pro-inflammatory mediators. Examples are summarized in this figure, which illustrates how macrophages ingest apoptotic cells, respond to AC-derived nutrients, and stimulate pro-resolving mediator production (e.g., TGFβ, IL-10, LXA₄) and the reduce the secretion of pro-inflammatory mediators (e.g., IL-1β, TNFα, LTB₄). SLC: Solute carrier (family) proteins; SGK: Serum and glucocorticoid-regulated kinase; PBX1: PBX homeobox 1; LAP: LC3-associated phagocytosis; ELMO: Engulfment and cell motility protein; DOCK180: Dedicator of cytokinesis protein 1; GULP: Engulfment adaptor phosphotyrosine-binding domain containing 1; Rac1: Ras-related C3 botulinum toxin substrate 1; PI3K/Akt: Phosphatidylinositol 3-kinase/Protein kinase B; TGFβ: Transforming growth factor beta; IL-10: Interleukin 10; LXA₄: lipoxin A₄; RvD1: Resolvin D1; IL-1β: Interleukin-1 beta; LTB₄: Leukotriene B₄; TNFα: Tumor necrosis factor alpha; CaMKIIγ: Calcium/calmodulin-dependent protein kinase II gamma; MAPK: Mitogen-activated protein kinase; ADAM17: A disintegrin and metalloproteinase 17; MK2: MAPK-activated protein kinase 2; MerTK: MER proto-oncogene tyrosine kinase; BAI1: Brain-specific angiogenesis inhibitor 1; AXL: AXL Receptor Tyrosine Kinase; LRP1: Low-density lipoprotein receptor-related protein 1; SERCA2: ATPase sarcoplasmic/endoplasmic reticulum Ca2⁺ transporting 2; ABCA1: ATP-binding cassette transporter A1; p-ERK: Phosphorylated extracellular signal-regulated kinase; AhR: Aryl hydrocarbon receptor; PTGS2: Prostaglandin-endoperoxide synthase 2; ODC: Ornithine decarboxylase 1; HuR: Human antigen R; DRP1: Dynamin-related protein 1.

Amino acid metabolism:

Studies have highlighted the critical role of amino acid metabolism after efferocytosis by macrophages³⁶. For example, impaired glutamine metabolism to glutamate via glutaminase (GLS) 1-mediated glutaminolysis impairs efferocytosis. Mechanistically, this non-canonical transaminase pathway channels glutamates into the malate-aspartate shuttle, fueling mitochondrial OXPHOS and ATP production to support the high-energy demand for F-actin remodeling⁵¹. Notably, ACs are rich in amino acids, and macrophages metabolize these substrates after their degradation to continue efferocytosis and resolve inflammation. For example, arginine is converted by arginase 1 (Arg1) into ornithine, which is then metabolized by ornithine decarboxylase (ODC1) into the polyamine putrescine⁵². Putrescine activates HuR-mediated stabilization of Mcf2 mRNA, leading to enhanced Dbl expression, Rac1 activity, and uptake of multiple dead cells (Figure 1)⁵². Similarly, tryptophan metabolism is directed by the indoleamine 2,3-dioxygenase 1 (IDO1) pathway, whereby AC-derived tryptophan is catabolized into kynurenine and related metabolites that engage the aryl hydrocarbon receptor (AhR)⁵³. AhR signaling not only promotes Rac1 activation to sustain efferocytosis but also drives the expression of pro-resolving mediators such as TGFβ, IL-10, and IDO1, thereby establishing a self-reinforcing feed-forward loop (Figure 1)⁵³. AC-derived methionine imposes a distinct layer of epigenetic control⁵⁴. Following engulfment, methionine is metabolized through DNMT3A to drive DNA methylation of negative feedback regulators such as DUSP4. This repression sustains ERK1/2 activation that drives resolution programming (Figure 1)⁵⁴. In this way, metabolism of AC-derived methionine directly reshapes the epigenetic landscape of efferocytes to maintain pro-resolving functions. Collectively, these amino acid pathways demonstrate that the metabolism of AC-derived amino acids sustain continual efferocytosis and drive inflammation resolution.

Nucleotide Metabolism and Macrophage Proliferation:

Nucleotides represent another abundant class of AC-derived cargo. Rather than being passively degraded, efferocytes recycle these substrates into metabolic pathways that drive cell cycle entry. This process, termed “efferocytosis-induced macrophage proliferation (EIMP)”, enables a unique form of local self-renewal within the plaque microenvironment⁵⁵. Mechanistically, AC-derived nucleotides cooperate with MerTK-ERK1/2 signaling to activate Myc, a master regulator of proliferation. In parallel, mTORC2 activity converges on this axis to further amplify Myc expression (Figure 1)⁵⁵. The net effect is the clonal expansion of pro-resolving macrophages, ensuring that efferocytes with high capacity for continual engulfment and anti-inflammatory cytokine production remain enriched in stable atherosclerotic lesions⁵⁵.

Glycolysis and Lactate Signaling:

Traditionally, glycolysis in macrophages is associated with a proinflammatory phenotype⁵⁶. However, AC engulfment induces aerobic glycolysis to drive resolution rather than inflammation (Figure 1)^57,58. This shift is explained by the role of lactate as a paracrine pro-resolving factor^57,58. Efferocytosis programs the expression of specific solute carrier (SLC) transporters, with SLC2A1 (GLUT1) mediating glucose uptake and SLC16A1 exporting lactate into the extracellular space⁵⁸. Exported lactate can signal via GPR132 to drive SIRT1-mediated Myc protein deacetylation and stabilization to drive EIMP⁵⁹. Further, lactate released into the plaque microenvironment fosters communication with other immune cells, promoting the secretion of resolving mediators and increasing the expression of AC receptors^57,58. Upstream, SGK1 and Akt signaling stabilize GLUT1 and activate phosphofructokinase, sustaining glycolytic flux⁵⁷. Phosphorylation of PFKFB2 by Akt further increase fructose-2,6-bisphosphate, an allosteric activator of glycolysis⁵⁷. Through these mechanisms, AC engulfment reprograms glycolysis from a proinflammatory pathway into one that fuels efferotabolism and resolution programming. Interestingly, under chronic physiological hypoxia (1% oxygen), macrophages shunt glucose into the noncanonical pentose phosphate pathway (PPP) loop⁶⁰. This unconventional utilization of glucose enhances NADPH production both prior to and during efferocytosis, promoting phagolysosomal acidification and cellular redox homeostasis^36,60.

Causes and Consequences of Impaired Efferocytosis

Atherosclerosis:

Defects in efferocytosis play a causal role in the development and progression of atherosclerosis by fueling non-resolving inflammation. These impairments arise from multiple converging mechanisms. For example, the TAM family of receptors undergo cleavage by ADAM metalloproteinases⁶¹, which are induced by inflammatory cues such as Toll-like receptor activation. The resulting soluble receptor fragment acts as a decoy, reducing surface receptor availability and sequestering bridging molecules necessary for efficient AC clearance^62–66. Interestingly, HMGB1 can also function as a damage-associated molecular pattern (DAMP) by binding and masking PtdSer on dying cells⁶⁷, while simultaneously suppressing expression of LRP1⁶⁸. Under normal conditions, AC-derived reactive oxygen species (ROS) oxidize HMGB1 and convert it into a tolerogenic signal⁶⁹, but in chronic inflammatory environments this protective process is lost. Likewise, bridging molecules such as Gas6 and Protein S are diminished in atherosclerosis, further compromising efferocytosis^70–73.

Genetic studies have revealed that defective efferocytosis can also be inherited. Individuals with a genetic variation on the cardiovascular disease risk locus on chromosome 9p21 show reduced calreticulin expression within plaques, and deletion of its receptor LRP1 in either macrophages or smooth muscle cells accelerates atherosclerosis^74–77. Similarly, phosphatase and actin regulator 1 (PHACTR1), which promotes efferocytosis, is downregulated in carriers of another CAD-linked risk allele⁷⁸. Disruption of inhibitory checkpoint pathways also contributes, with CD47 serving as a prominent “don’t-eat-me” signal. CD47 is markedly upregulated in human and murine atherosclerotic plaques, where it suppresses efferocytosis through engagement of its receptor SIRPα^27,79–81. Interestingly, statin therapy reduces CD47 expression, suggesting that part of its pleiotropic benefit may derive from enhancing efferocytosis and attenuating inflammation⁸². The pathological consequences of these defects are especially evident in atherosclerosis, where impaired efferocytosis drives the development of necrotic cores, acellular regions filled with lipids, debris, and dying cells that are normally removed by phagocytes⁸³. Thus, impaired efferocytosis establishes a vicious cycle: defective clearance promotes necrotic core expansion, necrotic debris amplifies inflammation, fibrous cap stability is lost, and the likelihood of rupture and acute cardiovascular events escalates.

Consequences in Myocardial Infarction:

Myocardial infarction (MI) causes massive death of cardiomyocytes and resident cardiac macrophages due to reperfusion-induced stress and necrosis. In response, circulating monocytes are rapidly recruited to the injured heart, where they adopt a pro-inflammatory phenotype but later transition into pro-resolving macrophages that clear dead cells and support tissue repair^84,85. Efferocytic macrophages promote myofibroblast activation, ECM production, and scar formation⁸⁶. When efferocytosis is impaired, fibroblasts receive insufficient cues for differentiation and ECM deposition, thereby directly contributing to maladaptive fibrosis post-MI. Interestingly, excessive or disorganized fibrosis may contribute to increased arrythmias⁸⁷. Efferocytic macrophages also produce factors like VEGF that encourage angiogenesis in the infarcted area⁸⁸. However, mounting evidence shows that efferocytosis is impaired post-MI in the human heart, with MerTK being necessary for apoptotic cardiomyocyte clearance^4,89,90. CD47 expression is also elevated in the post-MI heart, and administration of a CD47 blocking antibody during reperfusion enhanced efferocytosis, reduced inflammation and infarct size, and maintained cardiac contractile function⁹¹. Altogether, impaired efferocytosis facilitates the expansion of the infarct, aberrant fibrosis, and heart failure.

Vascular Aging and Aneurysm:

Vascular aging is characterized by endothelial dysfunction, arterial stiffening, and remodeling of the vessel wall. These factors impede blood flow and enhance shear stress, increasing the risk for aneurysm. As the vasculature ages, efferocytosis becomes progressively less efficient, leading to dead cell accumulation⁹². Secondary necrosis and subsequent release of DAMPs perpetuate chronic and unresolved inflammation, which has been termed “inflammaging.” In addition to hampered production of TGFβ and IL-10, aged efferocytes produce lower levels of “specialized pro-resolving mediators (SPMs)”, including resolvins and maresins, exacerbating MerTK cleavage and leukocyte infiltration into tissue⁹³. Senescent cell-mediated efferocytosis suppression (SCES) is a contact-dependent mechanism by which upregulation of CD47 on the senescent cell prevents macrophage engulfment via upregulation of the SHP-1 signaling pathway²³. Additionally, senescence-associated secretory phenotype (SASP) describes the release of pro-inflammatory cytokines, proteases, and ROS by senescent cells that ultimately drives chronic inflammation and vascular dysfunction with age⁹⁴. Moreover, the adhesion molecules ICAM-1 and VCAM-1 are upregulated in response to ROS, further promoting leukocyte recruitment⁹⁵. In the context of aneurysm, impaired efferocytosis and post-apoptotic necrosis enhance release of matrix metalloproteinases (MMPs) that degrade the ECM, thinning vessel walls; and notably, MMPs are elevated in human aneurysms⁹⁶. Thus, in aging vasculature, defective efferocytosis can promote inflammaging and arterial stiffening, ultimately impeding blood flow and increasing the risk of aneurysm.

Cardiometabolic Diseases:

Impaired efferocytosis has also been identified in numerous metabolic conditions characterized by chronic, low-grade inflammation, including obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). In obese adipose tissue, macrophages surround dead adipocytes in “crown-like structures” (CLS). The abundance of CLS in human adipose is positively correlated hyperinsulinemia, vascular dysfunction, and insulin resistance⁹⁷, and is associated with impaired efferocytosis. Importantly, apoptosis of pancreatic islet β cells is a defining feature of type 2 diabetes. Persistent hyperglycemia promotes advanced glycation end product (AGEs) formation, which inhibits macrophage efferocytosis through decreased Rac1 activity⁹⁸. In MASLD, hepatocyte apoptosis is abundant, with lipid-laden resident and recruited macrophages showing defective efferocytosis^99–101. As in atherosclerosis, the formation of lipid-associated macrophages (LAMs) has been described in numerous cardiometabolic conditions and can participate in dead cell clearance¹⁰², before becoming overwhelmed with lipid and undergoing apoptosis themselves. While foam cells are not inherently inflammatory, their loss of efferocytic capacity exacerbates secondary necrosis and inflammation within the affected tissue.

Emerging Concepts, Therapeutic Strategies, and Future Directions

Non-Professional Phagocytes:

Mounting evidence demonstrates that non-professional phagocytes, including vascular smooth muscle cells, fibroblasts, and endothelial cells can perform efferocytosis. In contrast to professional phagocytes, however, these cell types engulf and degrade apoptotic cells less efficiently and have a limited capacity for continual engulfment. Non-professional phagocytes may activate a functional program in response to efferocytosis that varies more with tissue-specific conditions, whereas efferocytosis by macrophages generally induces an anti-inflammatory cell profile; evidence supports that efferocytosis by these cells can promote pro-inflammatory signaling in some contexts. Non-professional phagocytes may also engage a more limited repertoire of efferocytic receptors compared to professional efferocytes. Importantly, macrophages help orchestrate efferocytosis by these non-professional phagocytes¹⁰³. In particular, vSMCs clear neighboring apoptotic vSMCs in a physiological setting¹⁰⁴. Surface calreticulin has also been identified as a ligand for efficient efferocytosis of vSMCs⁷⁴. If not properly cleared, apoptotic vSMCs can undergo secondary necrosis, releasing IL-1β and IL-6 and perpetuate inflammation¹⁰⁵. However, whether targeting vSMC-specific efferocytosis represents a viable therapeutic approach in atherosclerosis remains to be determined.

Fibroblasts, particularly cardiac myofibroblasts, are another non-professional phagocytic cell that have been implicated in AC clearance¹⁰⁶. Furthermore, this fibroblast population increased production of TGFβ and decreased production of IL-6 when challenged with LPS following efferocytosis. Fibroblasts capable of MFG-E8-mediated efferocytosis have also been identified in the skin and may play an important role in diabetic would healing¹⁰⁷. Keratocytes, the most populous cells in the cornea, undergo TGFβ-mediated differentiation into fibroblasts in response to injury and demonstrate phagocytic capacity¹⁰⁸. However, the specific function of these cells in vivo is an active area of investigation.

Subpopulations of ECs are also capable of efferocytosis, including those in the liver¹⁰⁹, high endothelial venules¹¹⁰, and microvasculature¹¹¹. One study showed that necrotic trophoblasts can activate and be engulfed by endothelial cells in culture¹¹². This finding may have implications at the maternal-fetal interface, where dead trophoblasts shed from the placenta that are not efficiently cleared can occlude capillaries and exacerbate preeclampsia in pregnancy. In the mouse aorta, ECs participate in efferocytosis and express high levels of MerTK. However, ECs lose MerTK expression during vascular aging and their capacity to internalize dead cells is diminished. A subsequent study showed that shear stress can also disrupt EC expression of MerTK, and that MerTK-deficient mice displayed abnormal EC thickening, decreased EC efferocytosis, and accelerated atherosclerosis¹¹³. A recent study of human aortic aneurysm also identified that MerTK expression is downregulated in ECs and is associated with increased inflammation, reduced efferocytic capacity, and worse disease outcomes¹¹⁴.

Crosstalk with Adaptive Immunity:

The role of efferocytosis in adaptive immunity is an area of growing interest. Conventional type 1 dendritic cells (cDC1s), specialized in cross-presentation and CD8⁺ T cell activation, preferentially engulf ACs via TAM receptors¹¹⁵. Once internalized, AC-derived antigens can be processed and presented¹¹⁶, leading to divergent T cell responses depending on the tissue microenvironment and the cargo. Under homeostatic conditions, ACs suppress DC maturation by reducing costimulatory molecules, inflammatory cytokines, and TLR signaling, thereby favoring tolerance^117–119. However, apoptotic material from infected or malignant cells promotes DC activation and immunogenic T cell priming^120,121. These findings highlight that efferocytosis is not merely corpse clearance but a checkpoint that can direct immunity toward tolerance or activation. This tolerogenic bias, however, is not absolute. Inflammatory cues such as TLR signaling can redirect AC-derived cargo into antigen presentation pathways, creating opportunities for autoreactive responses. This is particularly relevant in atherosclerosis, where oxLDL engages TLR4 on macrophages and DCs, potentially licensing presentation of AC antigens to autoreactive CD4⁺ T cells. The outcome is shaped by the balance of effector and regulatory CD4⁺ subsets. Supporting this duality, MHC class II deficiency in hyperlipidemic mice reduces CD4⁺ T cell numbers in plaques but paradoxically worsens disease, suggesting that loss of protective regulatory T cells outweighs reductions in pathogenic effectors¹²².

Notably, efferocytes/T-cell crosstalk drives the activation of regulatory T cells (Treg), suppresses effector T cell activity, and enhances efferocytosis¹²³. Pro-resolving mediators generated by efferocytes activate Tregs, which subsequently secrete TGFβ and IL-10^123,124. Mechanistic studies further demonstrate that these Tregs secrete IL-13, which induces IL-10 production by macrophages. Acting through an autocrine-paracrine loop, IL-10 triggers STAT3-dependent upregulation of Vav1, thereby activating Rac1 to promote AC engulfment^123,125.

Therapeutic Strategies and Future Directions:

Therapeutic targeting of efferocytosis in cardiovascular diseases requires strategies that both enhance AC recognition and sustain the downstream resolution programs initiated by engulfment. Widely used CVD drugs including lovastatin¹²⁶, atorvastatin⁷⁸, and losartan¹²⁷ have been shown in experimental models to enhance efferocytosis, suggesting that existing therapies can restore clearance of apoptotic cells, but more targeted strategies are also being explored. One approach is the pharmacologic activation of TAM family receptors using recombinant ligands or synthetic mimetics of bridging molecules. Gas6 mimetics can potentiate receptor phosphorylation, activate downstream Rac1-mediated actin remodeling, and amplify pro-resolving signaling cascades, thereby increasing the capacity of lesional macrophages to clear ACs. Beyond soluble ligands, receptor clustering using multivalent nanoparticles could further enhance TAM signaling strength and duration. A complementary line of investigation leverages nanoparticle- or liposome-based carriers designed to deliver pro-resolving lipid mediators (e.g. resolvins and maresins) or metabolic effectors that sustain efferocytic competence, such as polyamines or fatty acid oxidation substrates. Precision delivery platforms would enable co-delivery of phagocytic cues with resolving mediators to synergistically drive a pro-resolving macrophage phenotype. Another strategy would focus on preserving the integrity of AC-binding receptors by preventing their proteolytic shedding¹²⁸. Inhibitors of ADAM10/17 metalloproteases, for example, can limit MerTK cleavage, maintaining its surface expression and functionality. Gene therapy approaches encoding cleavage-resistant MerTK variants or constructs promoting receptor recycling represent a longer-term solution to sustain efferocytosis and limit necrotic core expansion, as has been demonstrated in preclinical models¹²⁹. Collectively, these strategies would aim to reprogram the plaque microenvironment toward sustained resolution and restore homeostasis.

However, several key gaps remain before efferocytosis-centered interventions can be translated into clinical cardiovascular therapeutics. First, there is an unmet need for reliable, non-invasive in vivo biomarkers capable of estimating efferocytic activity over time. Such tools, based on imaging of labeled AC surrogates, metabolic tracers linked to efferocytic cargo utilization, or soluble receptor fragments in plasma, would enable real-time monitoring of therapeutic efficacy. Second, integration of efferocytosis research with emerging concepts such as trained immunity and tissue-specific macrophage niches could uncover context-dependent pathways that shape macrophage phenotype. Third, the application of advanced multi-omics, including spatial transcriptomics, metabolomics, and proteomics, offers an unprecedented opportunity to resolve the spatial and temporal dynamics of phagocytes and their metabolic states within complex lesions^130–132. Such high-dimensional profiling in human disease samples will be critical for identifying cell-cell interactions and metabolic bottlenecks that limit resolution. Finally, any therapeutic manipulation of AC clearance must proceed with caution as overactivation of efferocytosis could inadvertently induce a premature resolution response that impairs immune surveillance against infected or transformed cells or provoke autoimmune responses if tolerance mechanisms are bypassed. Thus, a balanced approach will require modulation of efferocytosis and context-specific delivery systems in a manner that ensures resolution without compromising host defense.

Highlights.

• Efferocytosis is an active, immunometabolic program, coupling apoptotic cell clearance to metabolic reprogramming and inflammation resolution.

• Cargo-derived metabolites fuel “efferotabolism,” including lipid efflux, fatty acid oxidation, amino acid metabolism, and nucleotide recycling, each sustaining pro-resolving macrophage phenotypes.

• Defects in efferocytosis drive chronic inflammation and tissue injury across atherosclerosis, myocardial infarction, vascular aging, and metabolic diseases.

• Multiple molecular checkpoints regulate engulfment efficiency, including find-me/eat-me signals, receptor availability, proteolytic shedding, and metabolic bottlenecks.

• Targeting efferocytosis offers therapeutic potential, but requires balancing enhanced clearance with maintenance of immune surveillance and tissue-specific context.

Nonstandard Abbreviations and Acronyms

AC(s)

Apoptotic cell(s)

cDC1

Conventional type 1 dendritic cell

DAMPs

Damage-associated molecular patterns

EIMP

Efferocytosis-induced macrophage proliferation

FAO

Fatty acid oxidation

LAP

LC3-associated phagocytosis

PPP

Pentose phosphate pathway

PtdSer

Phosphatidylserine

SASP

Senescence-associated secretory phenotype

SCES

Senescent cell-mediated efferocytosis suppression

SPMs

Specialized pro-resolving mediators

TAM

Tyro3, AXL, MerTK receptor family

Treg

Regulatory T cell